Hepatic cirrhosis characterized by progressive liver fibrosis is one of the leading causes of morbidity from chronic abuse of ethanol worldwide. Hepatic stellate cells (abbreviated HSCs) are critical to this process. A central event leading up to fibrosis is the activation and transition of HSCs from a quiescent vitamin A-rich cell type to a vitamin A-deficient, proliferative, fibrogenic myofibroblast. Recent evidence suggests that cannabinoid receptors (abbreviated CBRs) are important to this process. While CB1R and CB2R are marginally expressed in normal liver, they undergo marked upregulation in the cirrhotic liver, predominantly in smooth muscle a-actin expressing cells within the fibrotic septa. Interestingly, CB1R is pro-fibrotic upon activation, whereas CB2R plays an anti-fibrotic role. Therefore, antagonism of CB1R is a rational approach to inhibit HSC activation and progression of fibrosis. Accordingly, a clinical trial examining the efficacy of the selective CB1R antagonist SR141716 in alcoholism sponsored by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) is underway. Unfortunately, chronic use of this medication may have undesirable adverse effects in patients particularly due to the activity of SR141716 in the central nervous system (abbreviated CNS). Thus, an effective strategy to target the CB1R that could by-pass some or most of these concerns is to develop peripherally active CB1R antagonists that cannot cross the blood-brain barrier (abbreviated BBB). This strategy would restrict the effect of CB1R antagonism to the periphery, and thereby eliminate the CNS-related concerns of chronically inhibiting central CB1R while retaining the beneficial antifibrotic potential of these compounds. Thus, we propose to synthesize and test peripherally active CB1R antagonists through the following two specific aims. Through aim 1, charged analogs of SR141716 bearing either a quaternary ammonium or an amino acid moiety will be synthesized and tested for antagonism of CB1Rs. This approach is based on the rationale that charged compounds do not cross the BBB, unless transported by specific transporters, in contrast to their neutral lipophilic analogs (i.e., SR141716) that can often penetrate the BBB by simple diffusion. Through aim 2, characterization of these compounds will be performed via three sub-aims. (a) The compounds will be tested for CB1R antagonism using a functional in vitro assay. (b) The ability of these compounds to cross the BBB will be studied in an in vitro predictive model of BBB transport. (c) The selectivity of these compounds for CB1R over CB2R using radioligand competition binding assays will be determined. In total, these studies are designed to synthesize and test the utility of SR141716 analogs as peripherally active CB1R antagonists, which may serve as early leads for therapeutics development for alcohol-induced liver fibrosis. [unreadable] [unreadable] [unreadable]